Medicine and Health Sciences Commons^™

Medical Sciences 4300: London-Middlesex Suicide Prevention Council, Harshith Bhaskar, Adnan Husein, Ramin Javaheri-Poya, Sabrina Jetly, Christopher Nguyen, Serena Tejpar

Community Engaged Learning Final Projects

Suicide is an issue that affects people of all backgrounds, and takes the lives of many individuals every year. The London-Middlesex Suicide Prevention Council (LMSPC), an organization established in 1990, seeks to provide suicide prevention training to members of the community. They seek to engage community members in prevention and intervention by recognizing warning signs that may exist among the London-Middlesex region. The three main programs that strive to deliver these skills are ASIST, ASK, and safeTALK, each with a slightly different focus. LMSPC’s current goal is to increase access to these services through external grants and potential partnerships. Our …

Prostate Cancer Microparticles In Men Undergoing Radical Prostatectomy, Malcolm James Dewar

Electronic Thesis and Dissertation Repository

Objectives: To determine changes in prostate microparticle (PMP) concentrations in men with prostate cancer (PCa) after digital rectal examination (DRE), after radical prostatectomy (RP), and at follow-up.

Materials and Methods: 22 men were recruited before RP. Four blood specimens were collected – baseline (specimen 1), post-DRE (specimen 2), immediately post-RP (specimen 3), and follow-up (specimen 4). Pre- and post-DRE urine was collected (Specimen A and B respectively). Flow cytometric analysis of biofluids was performed with fluorescent-labeled antibodies against prostate-specific membrane antigen (PSMA) and polysialic acid. Total MP (TMP) and dual positive (PMP) events per µl of plasma or urine were …

Hepcidin-Mediated Iron Regulation In P19 Cells Is Detectable By Mri, Kobra Alizadeh Pourbouyeh

Electronic Thesis and Dissertation Repository

Magnetic resonance imaging (MRI) can be used to track cellular activities in the body using iron-based contrast agents. However, intrinsic cellular iron handling mechanisms may also influence the detection of magnetic resonance (MR) contrast. For instance, inflammation involves downregulation of iron export in macrophages by the hormone hepcidin, due to degradation of the iron export protein, ferroportin (Fpn). We examined the effect of hepcidin on iron regulation and MR transverse relaxation rates in multi-potent P19 cells, which display high iron export activity, similar to macrophages. In response to varying conditions of iron supplementation, our results showed similar Fpn expression in …

Proteomic Characterization Of Human Multipotent Stromal Cells Secreted Proteins With Therapeutic Potential For Β-Cell Regeneration, Miljan Kuljanin

Electronic Thesis and Dissertation Repository

Novel strategies to stimulate the expansion of β-cell mass in situ are warranted for diabetes therapy. Cell-replacement therapies for the treatment of diabetes have become a focal point in recent years. Endogenous regeneration of β-cell mass has been demonstrated using human multipotent stromal cells (hMSC). However, the secretory factors responsible for initiating endogenous regeneration remain unknown. Successful large-scale proteomic applications to address these questions have been limited in part by difficulties in correctly selecting the appropriate methodologies. Thus, the goal of this thesis was a combination of assessing different proteomic workflows to facilitate investigation into hMSC biology, applying these methods …

Crispr Screen For Identification Of Kinases That Mediate Prostate Cancer Cell Invasion, Hamad Aldhafeeri

Electronic Thesis and Dissertation Repository

Metastasis is the primary cause of mortality in cancer patients. Inhibition of proteins that are involved in the regulation of metastasis are expected to suppress metastasis and represent treatment targets. Our focus is on prostate cancer metastasis and we have developed a novel high-throughput means of performing in vitro screens for regulators of prostate cancer metastasis. We propose to use a focused CRISPR library screen that will “knock out” all human kinases to determine which ones are responsible for prostate cancer metastasis. CRISPR is a potent genetic editing tool and was used to silence all kinases in prostate cells (BPH …

Neuronal Correlates For Neuroendocrine Habituation To Repeated Stress, Sara Matovic

Electronic Thesis and Dissertation Repository

One way that the body actively responds to an impending stressor is by increasing systemic glucocorticoids through the activation of the hypothalamic-pituitary-adrenal (HPA) axis. While it is essential for short-term adaptation to stress, the sustained activation of the HPA axis during chronic stress can be detrimental and is linked to stress-related psychiatric conditions such as anxiety and depression. Therefore, it is important that the HPA axis adapts, or habituates, during chronic stress to minimize the negative consequences. Corticotropin releasing hormone (CRH) neurons in the paraventricular nucleus of the hypothalamus (PVN) function to assimilate incoming information from the stress circuitry and …

Coevolving Residues And The Expansion Of Substrate Permissibility In Laglidadg Homing Endonucleases, Thomas A. Mcmurrough

Electronic Thesis and Dissertation Repository

Genome-editing (GE) is a form of genetic engineering that permits the deliberate manipulation of genetic material for the study of biological processes, agricultural and industrial biotechnologies, and developing targeted therapies to cure human disease. While the potential application of GE is wide-ranging, the efficacy of most strategies is dependent upon the ability to accurately introduce a double-stranded break at the genomic location where alterations are desired. LAGLIDADG homing endonucleases (LHEs) are a class of mobile genetic element that recognize and cleave 22-bp sequences of DNA. Given this high degree of specificity, LHEs are powerful GE reagents, …

Evaluating Small Airways Disease In Asthma And Copd Using The Forced Oscillation Technique And Magnetic Resonance Imaging, Heather M. Young

Electronic Thesis and Dissertation Repository

Obstructive lung disease, including asthma and chronic obstructive pulmonary disease (COPD), is characterized by heterogeneous ventilation. Unfortunately, the underlying structure-function relationships and the relationships between measurements of heterogeneity and patient quality-of-life in obstructive lung disease are not well understood. Hyperpolarized noble gas MRI is used to visualize and quantify ventilation distribution and the forced oscillation technique (FOT) applies a multi-frequency pressure oscillation at the mouth to measure respiratory impedance to airflow (including resistance and reactance). My objective was to use FOT, ventilation MRI and computational airway tree modeling to better understand ventilation heterogeneity in asthma and COPD. FOT-measured respiratory system …

Higher And Lower Order Factor Analyses Of The Temperament In Middle Childhood Questionnaire., Yuliya Kotelnikova, Thomas M Olino, Daniel N Klein, Sarah V M Mackrell, Elizabeth P Hayden

Brain and Mind Institute Researchers' Publications

The Temperament in Middle Childhood Questionnaire (TMCQ) is a widely used parent-report measure of temperament. However, neither its lower nor higher order structures has been tested via a bottom-up, empirically based approach. We conducted higher and lower order exploratory factor analyses (EFAs) of the TMCQ in a large ( N = 654) sample of 9-year-olds. Item-level EFAs identified 92 items as suitable (i.e., with loadings ≥.40) for constructing lower order factors, only half of which resembled a TMCQ scale posited by the measure's authors. Higher order EFAs of the lower order factors showed that a three-factor structure (Impulsivity/Negative Affectivity, Negative …

Hippocampal Gaba Enables Inhibitory Control Over Unwanted Thoughts, Taylor W. Schmitz, Marta M. Correia, Catarina S. Ferreira, Andrew P. Prescot, Michael C. Anderson

Brain and Mind Institute Researchers' Publications

© 2017 The Author(s). Intrusive memories, images, and hallucinations are hallmark symptoms of psychiatric disorders. Although often attributed to deficient inhibitory control by the prefrontal cortex, difficulty in controlling intrusive thoughts is also associated with hippocampal hyperactivity, arising from dysfunctional GABAergic interneurons. How hippocampal GABA contributes to stopping unwanted thoughts is unknown. Here we show that GABAergic inhibition of hippocampal retrieval activity forms a key link in a fronto-hippocampal inhibitory control pathway underlying thought suppression. Subjects viewed reminders of unwanted thoughts and tried to suppress retrieval while being scanned with functional magnetic resonance imaging. Suppression reduced hippocampal activity and memory …

Developmental Origins Of Health And Disease: Current Knowledge And Potential Mechanisms, Daniel J. Hoffman, Rebecca M. Reynolds, Daniel B. Hardy

Physiology and Pharmacology Publications

Epidemiologic and clinical research has provided a large body of evidence supporting the developmental origins of health and disease (DOHaD), but there has been a relative dearth of mechanistic studies in humans due to the complexity of working with large, longitudinal cohorts. Nonetheless, animal models of undernutrition have provided substantial evidence for the potential epigenetic, metabolic, and endocrine mechanisms behind DOHaD. Furthermore, recent research has explored the interaction between the environment and the gastrointestinal system by investigating how the gut microbial ecology may impact the capacity for nutrient processing and absorption in a manner that may limit growth. This review …

Multiparametric Mri Changes Persist Beyond Recovery In Concussed Adolescent Hockey Players, Kathryn Y. Manning, Amy Schranz, Robert Bartha, Gregory A. Dekaban, Christy Barreira, Arthur Brown, Lisa Fischer, Kevin Asem, Timothy J. Doherty, Douglas D. Fraser, Jeff Holmes, Ravi S. Menon

BrainsCAN Publications

Objective: To determine whether multiparametric MRI data can provide insight into the acute and long-lasting neuronal sequelae after a concussion in adolescent athletes.

Methods: Players were recruited from Bantam hockey leagues in which body checking is first introduced (male, age 11–14 years). Clinical measures, diffusion metrics, resting-state network and region-to-region functional connectivity patterns, and magnetic resonance spectroscopy absolute metabolite concentrations were analyzed from an independent, age-matched control group of hockey players (n 5 26) and longitudinally in concussed athletes within 24 to 72 hours (n 5 17) and 3 months (n 5 14) after a diagnosed concussion.

Results: There were …

Nicotinamide Phosphoribosyltransferase In Smooth Muscle Cells And Aortic Integrity, Alanna R. Watson

Electronic Thesis and Dissertation Repository

The thoracic aortic wall can degenerate over time with catastrophic consequences. Vascular smooth muscle cells (SMCs) can resist and repair artery damage but their capacities decline with age and stress. Recently, production of NAD⁺ via nicotinamide phosphoribosyltransferase (Nampt) has emerged as a mediator of cell vitality. However, a role for Nampt in aortic SMCs in vivo is unknown. To study the role of Nampt in SMCs, mice with Nampt-deficient SMCs were generated. SMC-Nampt knockout mice were viable but had mildly dilated aortas. Infusion of angiotensin II led to aortic medial hemorrhage and dissection. SMCs had indicators of premature …

Disruption Of Hippocampal Multisynaptic Networks By General Anesthetics., Min-Ching Kuo, L Stan Leung

Physiology and Pharmacology Publications

BACKGROUND: Previous studies showed that synaptic transmission is affected by general anesthetics, but an anesthetic dose response in freely moving animals has not been done. The hippocampus provides a neural network for the evaluation of isoflurane and pentobarbital on multisynaptic transmission that is relevant to memory function.

METHODS: Male Long-Evans rats were implanted with multichannel and single electrodes in the hippocampus. Spontaneous local field potentials and evoked field potentials were recorded in freely behaving rats before (baseline) and after various doses of isoflurane (0.25 to 1.5%) and sodium pentobarbital (10 mg/kg intraperitoneal).

RESULTS: Monosynaptic population excitatory postsynaptic potentials at the …

A Longitudinal Study Of Tumour Metabolism Using Hyperpolarized Carbon-13 Magnetic Resonance Spectroscopic Imaging In A Preclinical Model Of Glioma, Heeseung Lim

Electronic Thesis and Dissertation Repository

Glioma is the most common and aggressive primary malignant brain tumour. Glioma is typically treated with surgery followed by radio/chemotherapy. Even with aggressive treatment, median survival time is expected to be ~12 to 15 months. Reoccurrence of glioma is almost inevitable, further threatening the well-being of patients who have already endured rigorous treatment. Therefore, it is paramount to choose the most effective therapy and to accurately determine outcome as early as possible to provide optimum end-of-life care. Tumours alter their metabolism in response to increasing energy demands, mainly through increased glycolysis and accompanying lactate production. This increases production of other …

Characterization Of An Orthotopic Rat Model Of Glioblastoma Using Multiparametric Magnetic Resonance Imaging And Bioluminescence Imaging, Trung Le

Electronic Thesis and Dissertation Repository

Glioblastoma multiforme (GBM) is a lethal and incurable disease. The C6 rat model of GBM shares several similarities to human GBM and longitudinal non-invasive imaging may allow tumour features to be studied. In this thesis, a multimodality imaging framework, consisting of bioluminescence imaging (BLI) and multiparametric magnetic resonance imaging (mpMRI), was applied to the C6 rat model to characterize the growth of orthotopic tumours. BLI signal, a measure of cell viability, tended to increase and then decrease in the majority of animals, whereas tumour volume (from MRI) continually increased. Cellular viability and tumour volume did not correlate across all days, …

The Large-Scale Organization Of Shape Processing In The Ventral And Dorsal Pathways, Erez Freud, Jody C. Culham, David C. Plaut, Marlene Behrmann

Brain and Mind Institute Researchers' Publications

Although shape perception is considered a function of the ventral visual pathway, evidence suggests that the dorsal pathway also derives shape-based representations. In two psychophysics and neuroimaging experiments, we characterized the response properties, topographical organization and perceptual relevance of these representations. In both pathways, shape sensitivity increased from early visual cortex to extrastriate cortex but then decreased in anterior regions. Moreover, the lateral aspect of the ventral pathway and posterior regions of the dorsal pathway were sensitive to the availability of fundamental shape properties, even for unrecognizable images. This apparent representational similarity between the posterior-dorsal and lateral-ventral regions was corroborated …

Vocabulary Learning Benefits From Rem After Slow-Wave Sleep., Laura J Batterink, Carmen E Westerberg, Ken A Paller

Brain and Mind Institute Researchers' Publications

Memory reactivation during slow-wave sleep (SWS) influences the consolidation of recently acquired knowledge. This reactivation occurs spontaneously during sleep but can also be triggered by presenting learning-related cues, a technique known as targeted memory reactivation (TMR). Here we examined whether TMR can improve vocabulary learning. Participants learned the meanings of 60 novel words. Auditory cues for half the words were subsequently presented during SWS in an afternoon nap. Memory performance for cued versus uncued words did not differ at the group level but was systematically influenced by REM sleep duration. Participants who obtained relatively greater amounts of REM showed a …

Accumulation Of Non-Numerical Evidence During Nonsymbolic Number Processing In The Brain: An Fmri Study, Tali Leibovich, Daniel Ansari

Brain and Mind Institute Researchers' Publications

Behavioral evidence has shown that when performing a nonsymbolic number comparison task (e.g., deciding which of two dot arrays contains more dots), participants' responses are sensitive to affected by both numerical (e.g., number of items) and non-numerical magnitudes (i.e., area, density, etc.). Thus far it is unclear what brain circuits support this process of accumulating non-numerical variables during nonsymbolic number processing. To investigate this, 21 adult participants were asked to engage in a dot comparison task. To measure the neural correlates of accumulating numerical and non-numerical variables, we manipulated the number of the non-numerical magnitudes that were congruent (correlated with …

A Clinico-Pathological Study Of The Structural And Functional Changes In The Retina And Optic Nerve Following Diabetic Retinopathy Treatments, Richard Filek

Electronic Thesis and Dissertation Repository

Diabetic retinopathy (DR) is the result of microvascular changes in the retina due to hyperglycemia which alter the blood-retinal barrier (BRB). The increased permeability of BRB results in the accumulation of extracellular fluid, the development of diabetic macular edema (DME) and capillary occlusion. Capillary occlusion results in retinal ischemia which increases vascular endothelial growth factor (VEGF) levels, increases vascular permeability and results in neovascularization in proliferative diabetic retinopathy (PDR) patients. The treatments clinically used for DR are panretinal photocoagulation (PRP) for PDR and injectable vascular endothelial growth factor inhibitors (anti-VEGFs) for DME.

The safety of PRP and anti-VEGF therapy on …

Retinoic Acid Pathway Inhibition To Expand Human Hematopoietic Progenitor Cells With Islet Regenerative Capacity, Ruth Elgamal

Electronic Thesis and Dissertation Repository

Cellular therapy to induce islet regeneration is emerging as a novel treatment strategy for diabetes. Umbilical cord blood (UCB)-derived hematopoietic stem/progenitor cells (HSPC) isolated by high aldehyde dehydrogenase activity (ALDH^hi) reduce hyperglycemia after transplantation into streptozotocin (STZ)-treated NOD/SCID mice. However, UCB-derived ALDH^hi cells are rare and expansion without the loss of regenerative function is required. We hypothesized that BMS 493, an inverse retinoic acid receptor agonist, will prevent HSPC differentiation of HSPC during expansion, generating more ALDH^hi cells for therapy. ALDH^hi cells expanded for 6 days with BMS 493 showed a 2.70-fold-increase in ALDH^{hi …}

Pannexins 1 And 3 In Skeletal Health And Osteoarthritis, Paxton M. Moon

Electronic Thesis and Dissertation Repository

Osteoarthritis (OA) is a disease that gradually robs affected individuals of their mobility and places a substantial burden on health care systems and economies. OA results from pathological changes in bone, cartilage, synovium and supporting structures which are all essential to joint function. Cartilage degeneration, a hallmarking feature of OA, is an irreversible and untreatable consequence of these changes. Though the mechanisms underlying the initiation of cartilage breakdown remain unclear, joint injury and aging are risk factors. Pannexins (PANXs), a novel family of channel forming glycoproteins, have been suggested as important mediators of early OA. Therefore, my thesis tested the …

Amelioration Of Prenatal Alcohol Effects By Environmental Enrichment In A Mouse Model Of Fasd, Aniruddho Chokroborty-Hoque

Electronic Thesis and Dissertation Repository

Maternal alcohol consumption during pregnancy results in a spectrum of behavioural and cognitive deficits collectively known as Fetal Alcohol Spectrum Disorders (FASD). Currently, little is know about if and how the external environment may modulate these deficits. I have used C57BL/6 mice to study this interaction between prenatal alcohol exposure and the postnatal environment. Alcohol exposure during synaptogenesis produces high levels of anxiety-like traits and decreased memory performance. Alcohol-exposed mice (and matched unexposed controls) were put in 'environmentally-enriched' conditions of voluntary exercise, physical activities and cognitive stimulation to ascertain the effects of a positive postnatal environment. The results show that …

Functional Magnetic Resonance Imaging As An Assessment Tool In Critically Ill Patients, Loretta Norton

Electronic Thesis and Dissertation Repository

Little is known about whether residual cognitive function occurs in the earliest stages of brain injury. The overarching goal of the work presented in this dissertation was to elucidate the role of functional neuroimaging in assessing brain activity in critically ill patients. The overall objective was addressed in the following four empirical chapters: In Chapter 2, three versions of a hierarchically-designed auditory task were developed and their ability to detect various levels of auditory language processing was assessed in individual healthy participants. The same procedure was then applied in two acutely comatose patients. In Chapter 3, a hierarchical auditory task …

Immunological Impact Of Cli-095 On Dendritic Cell Maturation And Hypoxia-Re-Oxygenation Induced Inflammatory Injury, Hajed Obaid Alharbi

Electronic Thesis and Dissertation Repository

Immunological Impact of CLI-095 on Dendritic Cell Maturation and Hypoxia-re-oxygenation induced inflammatory injury

Introduction: Ischemia reperfusion injury (IRI) activates innate immunity through the engagement of Toll-Like Receptors (TLRs) by endogenous ligands. TLR4 expressed within the kidney is a potential mediator of innate activation and inflammation. Stimulation of TLR4 induces distinct patterns of gene expression, which not only leads to the activation of innate immunity but also to the development of acquired immunity. CLI-095, a novel synthetic small-molecule, suppresses production of multiple cytokines by inhibiting TLR4 signaling. In this study, we have determined the role of TLR4 in hypoxia and re-oxygenation …

Electrospun Collagen Nanofibers For Tissue Engineering, Nisha Sharma

Electronic Thesis and Dissertation Repository

Design and fabrication of the scaffold is an important part of the tissue engineering process. Nanofibrous scaffolds based on proteins are gaining increasing acceptance due to its structural similarity to the extracellular matrix. Making use of the electrospinning technique, rat tail collagen type I nanofibers were produced using a collagen in hexafluoroisopropanol (HFIP) solution. In addition to optimizing the electrospinning process parameters, the effect of humidity on fiber morphology and diameter was investigated for fiber size control for particular tissue engineering applications. A generalized humidity effect on polymer fiber diameter of the polymer solution electrospinning process was developed. The as …

Nicotinamide Riboside And The Aortic Response To Angiotensin Ii Infusion In Mice, Sina A. Ghoreishi

Electronic Thesis and Dissertation Repository

Damage to vascular cells of the aorta drives vascular dysfunction and disease. Nicotinamide adenine dinucleotide (NAD⁺) is a cellular metabolite critical to cellular health, but NAD⁺ levels decline during oxidative insults and aging. The NAD⁺ precursor, nicotinamide riboside (NR) can augment NAD⁺ levels. Herein, I determined whether orally administrated NR could protect the aorta of middle-aged mice from acute and sustained angiotensin II (Ang II) infusion-induced damage. I demonstrate that orally administered NR can protect the aorta from damage imposed by Ang II.

Using Computed Tomography Perfusion To Evaluate The Blood-Brain-Barrier And Blood-Tumor-Barrier Response Following Focused Ultrasound Sonication With Microbubble Administration, Hassaan Ahmed

Electronic Thesis and Dissertation Repository

The blood-brain-barrier (BBB) is the single most limiting factor in the delivery of neurotherapeutics into the brain. Focused ultrasound sonication combined with intravenous microbubble administration (FUSwMB) is a novel technique that can transiently disrupt the BBB, with minimal vascular or tissue damage, allowing for localized drug delivery over the targeted region. The goals of this thesis are to: 1) use computed tomography (CT) perfusion to measure the permeability surface area product (PS) following USwMB in normal rabbits with an intact BBB, and 2) to evaluate the blood-tumor-barrier (BTB) PS response following FUSwMB in a C6 rat glioma model.

The Design, Fabrication, And Characterization Of Nanoparticle-Protein Interactions For Theranostic Applications, Wai Hei Tse

Electronic Thesis and Dissertation Repository

Theranostics, a combination of therapeutics and diagnostics, spans a spectrum of research areas to provide new opportunities in developing new healthcare technologies and medicine at affordable prices. Through employing a personalized medicine approach, biotechnology can be tailored to the needs of an individual. Applications of theranostics include drug delivery carriers capable of sustained drug release and targeted delivery, biosensors with high sensitivity and selectivity, and diagnostic relevant entities that can be incorporated into the former technologies. Nanotechnology provides a suitable foundation for theranostics to build upon due to material-based properties; magnetism, biocompatibility, and quantum effects to name a few. Purpose …

Angiogenesis And Neo-Microcirculatory Function In Diseased Tissue Revealed By Intravital Microscopy, Giovanni-Michele Arpino

Electronic Thesis and Dissertation Repository

Angiogenesis is the process of generating new blood microvessels. In adults, angiogenesis is fundamental to tumor biology and also to tissues rendered ischemic from vascular occlusion. Despite a promising appeal, strategies designed to simulate or otherwise modify the angiogenic process in adult tissues have yet to realize significant therapeutic potential. Importantly, understanding the structure and function of new microvascular networks formed in adult, diseased tissues is limited. In fact, it remains unknown if a new or regenerated microcirculation can effectively deliver oxygen to the tissue. The purpose of this thesis was to seek out novel determinants of functional angiogenesis and …